Diffuse osteosclerosis as a presentation of recurrent breast cancer: role of endothelin 1.

We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. INTRODUCTION: Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. METHODS: Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. RESULTS: The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. CONCLUSIONS: Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.

Impact of chemotherapy on survival in surgically resected retroperitoneal sarcoma.

BACKGROUND: The role of systemic chemotherapy (CT) in the multimodality treatment strategy for retroperitoneal sarcomas (RPS) remains controversial. We hypothesized that chemotherapy does not improve overall survival for patients with surgically resected RPS. METHODS: The National Cancer Database was used to identify all patients with RPS that underwent surgical resection from 1998 to 2011. Univariate and multivariable Cox proportional hazards modeling were used to assess overall survival (OS) and logistic regression was used for associations. Propensity score (PS) modeling was performed to create balanced cohorts for analysis. RESULTS: A total of 8653 patients with surgically resected RPS were identified; 1525 (17.6%) received CT; 10.6% of patients (n = 163) in the neoadjuvant setting. Factors associated with receipt of CT included moderate (OR 2.3) to poorly differentiated (OR 4.3) tumors, leiomyosarcoma (OR 1.8) or undifferentiated pleomorphic sarcoma (OR 2.3) histology, and R2 resection status (OR 2.2) (all p < 0.05). Unadjusted median OS for patients receiving CT compared to surgery alone was 40 vs 68.2 months respectively (p < 0.01). Following propensity score matching, worse median OS persisted among the CT cohort (40 vs 52 months, p = 0.002). Receipt of chemotherapy was not associated with improved long term survival in adjusted models for the raw and propensity matched cohorts (HR 1.17, 95% CI: 1.04-1.31; p = 0.009). CONCLUSION: Current available chemotherapy regimens for RPS do not confer a survival benefit. Routine use of chemotherapy for RPS should be discouraged until new effective systemic agents become available.

Drug monitoring of antiretroviral therapy for HIV-1 infection: method validation and results of a pilot study.

BACKGROUND: Antiretroviral therapy for HIV-1 infection has become increasingly complex. The availability of new and potent drugs and progress in understanding the pathogenesis of HIV-1 infection have led to the establishment of new treatment paradigms. The varying dosing regimens, associated toxicities, and the potential for drug-drug and food-drug interactions further complicate treatment. This complexity contributes to patient nonadherence. Because clinicians have no tools to monitor adherence or drug-drug interactions and because response requires that therapy exceed the known inhibiting concentration, serum monitoring of antiretroviral therapy may play a role in improving treatment of HIV-1 infection. We report methods to quantify serum concentrations of antiretroviral drugs used to treat HIV-1 infection, precision and interference studies of these methods, and results observed in a pilot evaluation of blood serum concentrations from 12 human subjects. METHODS: HPLC offers adequate sensitivity to measure peak or trough serum concentrations of delavirdine, lamivudine, nevirapine, indinavir, nelfinavir, ritonavir, and saquinavir and peak serum concentrations of stavudine, zidovudine, and didanosine with reasonable precision. RESULTS: Peak indinavir serum concentrations in most patients were in the range of 1-10 mg/L, and trough concentrations were in the range of 0.1-0.5 mg/L. Peak stavudine concentrations were in the range of 0.3-1.3 mg/L, and trough concentrations were in the range of 0.1-0.5 mg/L. Peak zidovudine concentrations were in the range of 0.1-1.1 mg/L. CONCLUSIONS: Because this was a blood serum concentration-seeking pilot study to evaluate analytic performance, we do not report on the correlation of drug response to blood concentration. However, the concentrations observed in patients are generally consistent with blood concentrations reported from studies of monotherapy.

A solid phase extraction method for determination of nicotine in serum and urine by isotope dilution gas chromatography/mass spectrometry with selected ion monitoring.

A rapid method for measuring nicotine concentration in serum and urine is described. Deuterated nicotine is used as an internal standard. Nicotine and deuterated nicotine are extracted using a copolymeric-bonded phase silica column. The extract is analysed by gas chromatography coupled with mass spectrometry (GC/MS) operating in selected ion monitoring mode. The method has a lower limit of detection of approximately 2 micrograms/L and is linear to at least 2000 micrograms/L. Within-run percentage coefficients of variation (% CV) are < 4 in both assays over a nicotine concentration range of 10-2000 micrograms/L. Between-run % CV in the serum assay are 5.4, 5.2, 4.8 and 5.9, respectively, at nicotine concentrations of 10, 15, 25, and 50 micrograms/L. Between-run % CV in the urine assay are 5.9, 4.5, 2.7 and 5.2, respectively, at nicotine concentrations of 100, 250, 500, and 2000 micrograms/L. The absolute recovery of nicotine is 61 +/- 6% (mean +/- SD) over the range of 10-250 micrograms/L. The assay has been used to measure serum nicotine concentrations and 24-h urinary excretion of nicotine to monitor the extent of replacement in subjects receiving transdermal nicotine therapy for smoking cessation.

Quality assessment and clinical research: a collaborative approach.

Obtaining physician commitment to and continued involvement in quality assessment activities can be difficult. Some physicians view quality assessment as a bureaucratic morass that fails to improve patient care. However, by combining quality assessment and clinical research, insight into practice patterns can be obtained and physicians might be more likely to express interest in quality assessment issues. We reviewed medical records of patients at our hospital on peritoneal dialysis (PD) to determine the rate of free air found in normal PD patients. This was compared to PD patients with known gastrointestinal perforation; free intra-abdominal air has been described as a sign of gastrointestinal perforation. Documentation of free air and its significance in radiology reports were noted. Fifty-nine of 59 (100%) cases had available radiology reports. Documentation of free air was present in only 5 of 23 (22%) cases, and its significance was noted in the same 5 of 23 (22%). These results were communicated within the hospital, and a subsequent improvement in free-air detection, documentation, and reporting--both oral and written--was noted by the clinical service. The documentation of radiological findings is a frequently used monitor in radiology quality assessment. Our study identified a clinical and documentation problem, quantified the deficiency, and took steps toward improvement while simultaneously performing clinical research. We conclude that quality assessment and clinical research can coexist and serve to improve clinical practice while encouraging physician involvement in quality assessment programs.

Automated HPLC assay of fluoxetine and norfluoxetine in serum.

This automated assay determines the concentration of the antidepressant fluoxetine (Prozac) and its active metabolite norfluoxetine in serum by reversed-phase HPLC with spectrophotometric detection. Extraction, injection, and quantification are performed by the Gilson Aspec automated sample handler. The patient's specimen, with added protriptyline as internal standard, is extracted with solid-phase and liquid-liquid methods. Separation is conducted isocratically on a 5-microns (particle size) Supelcosil LC-8-DB reversed-phase column with a triethylamine acetate:acetonitrile mobile phase. The detection limit is 10 micrograms/L and absorbance varies linearly with concentration between 20 and 1,000 micrograms/L for both compounds. Mean recovery was 62% for fluoxetine and 70% for norfluoxetine over linear limits. Within-run and day-to-day imprecision (CV), evaluated at three concentrations (50, 200, and 500 micrograms/L), ranged from 2% to 7%. An extensive interference study of 108 drugs was conducted. Results (n = 58) by the automated method (y) correlated well with those by a manual HPLC method (x): y = 0.96x + 10.20 (r = 0.951, Sylx = 42.9) for fluoxetine, and y = 0.95x - 1.37 (r = 0.917, Sylx = 47.2) for norfluoxetine.

Determining drug dispensing costs for use in cost-accounting systems.

Identification of pharmacy costs to be used in a university hospital's cost-accounting system (CAS) is described. At the University of Wisconsin Hospital and Clinics (UWHC), Madison, standard pharmacy labor times for seven categories of products were developed by determining the pharmacist and technician times for purchasing, ordering, transcribing orders, manufacturing, and distributing and administering medications; pharmacy technicians administer most of the medications to patients at UWHC. The labor cost per dose (standard time multiplied by average wage including fringe benefits) was added to drug acquisition cost, which was obtained from the hospital's computerized formulary. The direct costs associated with drug distribution were identified for use in the hospital CAS. These data can be used to compare the cost-effectiveness of various medication administration schedules; they may also be useful in productivity monitoring and flexible budgeting.

Marijuana testing--how good is it?

Testing for the use of marijuana necessitates one or more levels of assessment, depending on the clinical application of the test results. The EMIT-dau screening test with a sensitivity limit of 20 ng/ml is highly satisfactory for screening for the absence of marijuana in the urine. This test has a virtual 100% true-negative rate as long as an unadulterated urine specimen is analyzed. Positive results by the EMIT-dau procedure are presumptive because the test seems to produce false-positive results when applied to a random population of suspected drug users. In a population in a specific clinical environment such as in drug-treatment programs in which 20 of every 100 specimens will yield positive THC-COOH results by EMIT-dau screening, 3 (15%) of the 20 positive results will likely be false-positive. Our experience with the EMIT-dau suggests that of 100 test results, 3 will be false-positive, an overall 3% false-positive rate. If a positive test result will put the patient in considerable jeopardy and the screening result is the only evidence of drug use, confirmatory testing is imperative. Of the confirmatory tests, GC/MS seems to have the specificity necessary to provide a high level of confidence in the results. A combination of the EMIT procedure with a sensitivity level of 20 ng/ml and GC/MS confirmation yields virtually 100% accuracy in detection of marijuana abuse.

Improved chromatography of cyclosporine.

A fast liquid chromatographic procedure for the measurement of whole-blood cyclosporine concentration is described. A sample preparation using solid-phase extraction requires 5.5 min of technical effort per sample. Chromatographic development is complete in 6 min. The results of this procedure correlate with those of a previously validated procedure. The slope of the correlation equation is 1.04, the gamma-intercept is -17, and the correlation coefficient is 0.99. Reproducibility of the procedure at midtherapeutic concentration is 5.5%, and sensitivity is 25 ng/ml. No chemical interference was observed from 33 drugs commonly co-administered during immunosuppression.